Prostaglandin endoperoxide H synthase biosynthesis inhibitors

Abstract

The present invention describes pyridazinone compounds of formula I which are cyclooxygenase (COX) inhibitors, and in particular, are selective inhibitors of cyclooxygenase-2 (COX-2), COX-2 is the inducible isoform associated with inflammation, as opposed to the constitutive isoform, cyclooxygenase-1 (COX-1) which is an important “housekeeping” enzyme in many tissues, including the gastrointestinal (GI) tract and the kidneys. The selectivity of these compounds for COX-2 minimizes the unwanted GI and renal side-effects seen with currently markered non-steroidal anti-inflammatory drugs (NSAIDs).

1. A compound of formula I: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salt or ester thereof, wherein
 X is O; 
 R is alkyl or phenyl optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from the group consisting of halogen, alkyl, and haloalkyl; 
 R 1  is selected from the group consisting of carboxyalkylcarbonyloxyalkoxy, aminoalkylcarbonyloxyalkoxy, and phosphonatoalkoxy; 
 R 3  is hydrogen; 
 R 2  is selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         X 1  is S(O) 2 ; 
         X 2  is selected from the group consisting of hydrogen, alkyl and halogen; and 
         R 9  is selected from the group consisting of alkyl and amino. 
       
     
     
       2. A compound of  claim 1  wherein R is selected from the group consisting of tert-butyl, difluorophenyl, fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, chlorofluorophenyl, dichlorophenyl, 3-trifluoromethyl-4-fluorophenyl, and bromofluorophenyl. 
     
     
       3. A compound according to  claim 1  selected from the group consisting of
 2-(tert-butyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone; 
 3-({2-(3,4-difluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen phosphate; 
 3-({2-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen phosphate; 
 3-({2-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen phosphate; 
 3-({2-(3-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen phosphate; 
 3-({2-(3-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen phosphate; 
 3-({2-(3-bromophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen phosphate; 
 3-({2-(3-trifluoromethylphenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen phosphate; 
 3-({2-(3-chloro-4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen phosphate; 
 3-({2-(3-fluoro-4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen phosphate; 
 3-({2-(3,4-dichlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen phosphate; 
 3-({2-(3-trifluoromethyl-4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen phosphate; 
 3-({2-(3-bromo-4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen phosphate; 
 3-({2-(tert-butyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen phosphate; 
 2-(3,4-difluorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone; 
 2-(4-fluorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone; 
 2-(4-chlorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone; 
 2-(3-fluorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone; 
 2-(3-chlorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone; 
 2-(3-bromophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone; 
 2-(3-trifluoromethylphenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone; 
 2-(3-chloro-4-fluorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone; 
 2-(3-fluoro-4-chlorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone; 
 2-(3,4-dicholorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone; 
 2-(3-trifluoromethyl-4-fluorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone; 
 2-(3-bromo-4-fluorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone; 
 2-(tert-butyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone; 
 2-(3,4-difluorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone; 
 2-(4-fluorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone; 
 2-(4-chlorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone; 
 2-(3-fluorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone; 
 2-(3-chlorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone; 
 2-(3-bromophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4(methylsulfonyl)phenyl]-3(2H)-pyridazinone; 
 2-(3-trifluoromethylphenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone; 
 2-(3-chloro-4-fluorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone; 
 2-(3-fluoro-4-chlorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone; 
 2-(3,4-dichlorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone; 
 2-(4-fluoro-3-trifluoromethylphenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone; and 
 2-(3-bromo-4-fluorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone. 
 
     
     
       4. A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       5. A method for treating pain, fever, inflammation, rheumatoid arthritis and osteoarthritis comprising administering a compound of  claim 1 . 
     
     
       6. A compound of formula II: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof, wherein
 X is 0; 
 R is selected from the group consisting of pyridyl, benzothienyl, and thienyl; 
 R 1  is selected from the group of consisting of 2-hydroxy-2-propoxy and 3-hydroxy-3-methylbutoxy, 3-hydroxy-2-methyl-1-propoxy; and 3-hydroxy-1-butoxy; 
 R 3  is independently selected from the group consisting of alkoxyalkyl, alkyl, aminocarbonylalkyl, phenyl, benzyl, cyano, haloalkyl, and halogen; 
 R 2  is selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         X 1  is S(O) 2 ; 
         X 2  is selected from the group consisting of hydrogen, alkyl and halogen; and 
         R 9  is selected from the group consisting of alkyl and amino. 
       
     
     
       7. A compound according to  claim 6  wherein R 9  is methyl or amino; and R is pyridyl. 
     
     
       8. A pharmaceutical composition comprising a therapeutically effective amount of the compound of  claim 6  and a pharmaceutically acceptable carrier. 
     
     
       9. A method for treating pain, fever, inflammation, rheumatoid arthritis, and osteoarthritis comprising administering to a therapeutically effective amount of a compound of  claim 6 . 
     
     
       10. A method for treating pain, fever, inflammation, rheumatoid arthritis, and osteoarthritis comprising administering to a therapeutically effective amount of a compound of formula III 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof, wherein
 R is selected from the group consisting of a) alkyl, b) aryl, wherein the aryl is optionally substituted phenyl wherein said substituents are selected from alkyl, halogen, and haloalkyl, c) arylalkyl wherein the aryl of arylalkyl is optionally substituted phenyl wherein said substituents are selected from alkyl, halogen, and haloalkyl, d) haloalkyl, and e) haloalkenyl; 
 R 1  is hydroxyalkoxy; and 
 R 9  is selected from the group consisting of alkyl and amino.